The incidence of melanoma is rapidly increasing in the U.S. population. Within the under-35 age population, it has the highest incidence and mortality of all cancer types. Once melanoma has progressed to the invasive stage, it is difficult to cure, since there are very few effective chemotherapeutic agents. We have found that the plant polyphenol, resveratrol, present in grape skins, certain nuts and especially red wine, is a potent inducer of apoptosis in two human melanoma cell lines. We propose to test the hypothesis that resveratrol can inhibit the development/growth of human melanoma xenografts in nude mice. This will be investigated by three aims. First, we will determine if dietary administration of resveratrol prior to tumor cell inoculation can delay the onset of melanoma development. We will also investigate whether dietary administration of resveratrol can inhibit the growth of already established melanoma xenografts. If dietary administration has no effect, then we will determine if direct injection of resveratrol into the tumor site can inhibit melanoma xenograft growth. In the second aim we will investigate the metabolism of resveratrol and characterize its major metabolites in the athymic mouse. Special emphasis will be placed on the accumulation of resveratrol or metabolites in the skin and in the tumors. Lastly, we will begin studies on the molecular mechanism by which resveratrol induces apoptosis in human melanoma cell lines by using an apoptotic-specific gene array approach combined with a apoptotic-specific antibody array. These experiments should provide data to show whether resveratrol might be an effective in vivo chemo-preventive/therapeutic agent. Also the information derived from the metabolism and molecular mechanism studies could provide insights into improving/maximizing the biological activity of resveratrol.